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Objective: Elevated entorhinal cortex (EC) tau in low beta‐amyloid individuals can predict accumulation of pathology and cognitive decline. We compared the accuracy of magnetic resonance imaging (MRI)‐derived locus coeruleus integrity, neocortical beta‐amyloid burden by positron emission tomography (PET), and hippocampal volume in identifying elevated entorhinal tau signal in asymptomatic individuals who are considered beta‐amyloid PET‐negative. Methods: We included 188 asymptomatic individuals (70.78 ± 11.51 years, 58% female) who underwent 3T‐MRI of the locus coeruleus, Pittsburgh compound‐B (PiB), and Flortaucipir (FTP) PET. Associations between elevated EC tau and neocortical PiB, hippocampal volume, or locus coeruleus integrity were evaluated and compared using logistic regression and receiver operating characteristic analyses in the PiB− sample with a clinical dementia rating (CDR) of 0. Associations with clinical progression (CDR‐sum‐of‐boxes) over a time span of 6 years were evaluated with Cox proportional hazard models. Results: We identified 26 (21%) individuals with high EC FTP in the CDR = 0/PiB− sample. Locus coeruleus integrity was a significantly more sensitive and specific predictor of elevated EC FTP (area under the curve [AUC] = 85%) compared with PiB (AUC = 77%) or hippocampal volume (AUC = 76%). Based on the Youden‐index, locus coeruleus integrity obtained a sensitivity of 77% and 85% specificity. Using the resulting locus coeruleus Youden cut‐off, lower locus coeruleus integrity was associated with a two‐fold increase in clinical progression, including mild cognitive impairment. Interpretation: Locus coeruleus integrity has promise as a low‐cost, non‐invasive screening instrument to detect early cortical tau deposition and associated clinical progression in asymptomatic, low beta‐amyloid individuals. ANN NEUROL 2024;96:650–661 [ABSTRACT FROM AUTHOR]

Tau accumulation in and neurodegeneration of locus coeruleus (LC) neurons is observed in Alzheimer's disease (AD). We investigated whether tangle and neuronal density in the rostral and caudal LC is characterized by an asymmetric pattern in 77 autopsy cases of the Rush Memory and Aging Project. We found left-right equivalence for tangle density across individuals with and without AD pathology. However, neuronal density, particularly in the caudal-rostral axis of the LC, is asymmetric among individuals with AD pathology. Asymmetry in LC neuronal density may signal advanced disease progression and should be considered in AD neuroimaging studies of LC neurodegeneration. [ABSTRACT FROM AUTHOR]

Objective: While studies suggested that locus coeruleus (LC) neurodegeneration contributes to sleep–wake dysregulation in Alzheimer's disease (AD), the association between LC integrity and circadian rest‐activity patterns remains unknown. Here, we investigated the relationships between 24‐hour rest‐activity rhythms, cognitive trajectories, and autopsy‐derived LC integrity in older adults with and without cortical AD neuropathology. Methods: This retrospective study leveraged multi‐modal data from participants of the longitudinal clinical‐pathological Rush Memory and Aging Project. Indices of 24‐hour rest‐activity rhythm fragmentation (intradaily variability) and stability (interdaily stability) were extracted from annual actigraphic recordings, and cognitive trajectories were computed from annual cognitive evaluations. At autopsy, LC neurodegeneration was determined by the presence of hypopigmentation, and cortical AD neuropathology was assessed. Contributions of comorbid pathologies (Lewy bodies, cerebrovascular pathology) were evaluated. Results: Among the 388 cases included in the study sample (age at death = 92.1 ± 5.9 years; 273 women), 98 (25.3%) displayed LC hypopigmentation, and 251 (64.7%) exhibited cortical AD neuropathology. Logistic regression models showed that higher rest‐activity rhythm fragmentation, measured up to ~7.1 years before death, was associated with increased risk to display LC neurodegeneration at autopsy (odds ratio [OR] = 1.46, 95% confidence interval [CI95%]: 1.16–1.84, pBONF = 0.004), particularly in individuals with cortical AD neuropathology (OR = 1.56, CI95%: 1.15–2.15, pBONF = 0.03) and independently of comorbid pathologies. In addition, longitudinal increases in rest‐activity rhythm fragmentation partially mediated the association between LC neurodegeneration and cognitive decline (estimate = ‐0.011, CI95%: ‐0.023–‐0.002, pBONF = 0.03). Interpretation: These findings highlight the LC as a neurobiological correlate of sleep–wake dysregulation in AD, and further underscore the clinical relevance of monitoring rest‐activity patterns for improved detection of at‐risk individuals. ANN NEUROL 2024;95:653–664 [ABSTRACT FROM AUTHOR]

Introduction: Autopsy studies recognize the locus coeruleus (LC) as one of the first sites accumulating tau in Alzheimer's disease (AD). Recent AD work related in vivo LC magnetic resonance imaging (MRI) integrity to tau and cognitive decline; however, relationships of LC integrity to age, tau, and cognition in autosomal dominant AD (ADAD) remain unexplored. Methods: We associated LC integrity (3T‐MRI) with estimated years of onset, cortical amyloid beta, regional tau (positron emission tomography [PET]) and memory (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word‐List‐Learning) among 27 carriers and 27 non‐carriers of the presenilin‐1 (PSEN1) E280A mutation. Longitudinal changes between LC integrity and tau were evaluated in 10 carriers. Results: LC integrity started to decline at age 32 in carriers, 12 years before clinical onset, and 20 years earlier than in sporadic AD. LC integrity was negatively associated with cortical tau, independent of amyloid beta, and predicted precuneus tau increases. LC integrity was positively associated with memory. Discussion: These findings support LC integrity as marker of disease progression in preclinical ADAD. [ABSTRACT FROM AUTHOR]

The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We investigated whether elevated NE-metabolism alone predicts memory decline or whether concomitant presence of tau and amyloid-β is required. Among 114 memory clinic participants, time trends (max. six years) showed dose-response declines in learning across groups with elevated NE-metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) with no, one, or two Alzheimer's disease biomarkers; and no decline in the low MHPG group. Elevated MHPG is required and sufficient to detect learning declines, supporting a pathophysiologic model including the LC-NE system contributing to initial Alzheimer's disease-related processes. [ABSTRACT FROM AUTHOR]

The locus coeruleus (LC) plays a crucial role in modulating several higher order cognitive functions via its widespread projections to the entire brain. We set out to investigate the hypothesis that LC functional connectivity (FC) may fluctuate nonlinearly with age and explored its relation to memory function. To that end, 49 cognitively healthy individuals (19–74 years) underwent ultra high-resolution 7T resting-state functional magnetic resonance imaging and cognitive testing. FC patterns from the LC to regions of the isodendritic core network and cortical regions were examined using region of interest–to–region of interest analyses. Curvilinear patterns with age were observed for FC between the left LC and cortical regions and the nucleus basalis of Meynert. A linear negative association was observed between age and LC-FC and ventral tegmental area. Higher levels of FC between the LC and nucleus basalis of Meynert or ventral tegmental area were associated with lower memory performance from age of 40 years onward. Thus, different LC-FC patterns early in life can signal subtle memory deficits. Furthermore, these results highlight the importance of intact interactions between neurotransmitter systems for optimal cognitive aging. [ABSTRACT FROM AUTHOR]

Five decades ago, seminal studies positioned the brainstem locus coeruleus (LC) norepinephrine (NE) system as a key substrate for the regulation of wakefulness and sleep, and this picture has recently been elaborated thanks to methodological advances in the precise investigation and experimental modulation of LC structure and functions. This review presents and discusses findings that support the major role of the LC-NE system at different levels of sleep-wake organization, ranging from its involvement in the overall architecture of the sleep-wake cycle to its associations with sleep microstructure, while accounting for the intricate neuroanatomy surrounding the LC. Given the particular position held by the LC-NE system by being at the intersection of sleep-wake dysregulation and initial pathophysiological processes of Alzheimer's disease (AD), we conclude by examining emerging opportunities to investigate LC-NE mediated relationships between sleep-wake alteration and AD in human aging. We further propose several research perspectives that could support the LC-NE system as a promising target for the identification of at-risk individuals in the preclinical stages of AD, and for the development of novel preventive interventions. [ABSTRACT FROM AUTHOR]